Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University School of Medicine, Jerusalem 91120, Israel.
J Neurosci. 2013 Apr 3;33(14):6102-11. doi: 10.1523/JNEUROSCI.4023-12.2013.
In the nematode Caenorhabditis elegans, the heat shock response (HSR) is regulated at the organismal level by a network of thermosensory neurons that senses elevated temperatures and activates the HSR in remote tissues. Which neuronal receptors are required for this signaling mechanism and in which neurons they function are largely unanswered questions. Here we used worms that were engineered to exhibit RNA interference hypersensitivity in neurons to screen for neuronal receptors that are required for the activation of the HSR and identified a putative G-protein coupled receptor (GPCR) as a novel key component of this mechanism. This gene, which we termed GPCR thermal receptor 1 (gtr-1), is expressed in chemosensory neurons and has no role in heat sensing but is critically required for the induction of genes that encode heat shock proteins in non-neural tissues upon exposure to heat. Surprisingly, the knock-down of gtr-1 by RNA interference protected worms expressing the Alzheimer's-disease-linked aggregative peptide Aβ3-42 from proteotoxicity but had no effect on lifespan. This study provides several novel insights: (1) it shows that chemosensory neurons play important roles in the nematode's HSR-regulating mechanism, (2) it shows that lifespan and heat stress resistance are separable, and (3) it strengthens the emerging notion that the ability to respond to heat comes at the expense of protein homeostasis (proteostasis).
在秀丽隐杆线虫中，热休克反应（HSR）在生物体水平上受到一个由热敏神经元组成的网络的调节，这些神经元感知温度升高并在远程组织中激活 HSR。这种信号机制需要哪些神经元受体，以及它们在哪些神经元中起作用，在很大程度上仍是未解决的问题。在这里，我们使用了经过工程改造的线虫，这些线虫在神经元中表现出 RNA 干扰超敏性，用于筛选激活 HSR 所需的神经元受体，并鉴定出一种假定的 G 蛋白偶联受体（GPCR）作为该机制的一个新的关键组成部分。我们将这个基因命名为 GPCR 热敏受体 1（gtr-1），它在化学感觉神经元中表达，在热感中没有作用，但在暴露于热时，在非神经组织中诱导编码热休克蛋白的基因的表达中是必不可少的。令人惊讶的是，通过 RNA 干扰敲低 gtr-1 可以保护表达阿尔茨海默病相关聚集肽 Aβ3-42 的线虫免受蛋白毒性，但对寿命没有影响。这项研究提供了几个新的见解：（1）它表明化学感觉神经元在线虫的 HSR 调节机制中起着重要作用；（2）它表明寿命和耐热性是可分离的；（3）它增强了这样一种观点，即对热的反应能力是以蛋白质平衡（稳态）为代价的。
